Chemical disruption of the Hh and Wnt pathways in vertebrate development

描述(由申请人提供)：大量证据支持细胞对发育重要的信号分子的异常反应在癌症的生物发生中的作用。由于正常发育过程对这些通路的依赖，正在开发的针对这些通路的药物，例如那些由Hedgehog和Wnt信号分子控制的药物，在儿童或育龄妇女中的治疗价值可能会降低。我们研究的长期目标是了解使我们能够在对正常发育过程影响最小的情况下针对疾病中的这些途径的机制。在这个方案中，我们将以斑马鱼为模式生物，揭示HH和Wnt/2-catenin信号转导通路的两种新型抑制剂与脊椎动物发育组织的相互作用。在确定短暂暴露于这些小分子影响的发育过程中，我们将建立必要的知识库，以成功预测和减少针对这些发育途径和通常是癌症途径的治疗靶点所产生的有害影响。与公共卫生相关：在过去的十年中，在实现对关键的发育信号转导途径的化学控制方面取得了重大进展，这些信号转导途径经常在癌症中受到破坏。鉴于这些治疗策略的前景以及它们对发育中的个体构成的危险，我们建议系统地记录在脊椎动物胚胎发生和青少年生长过程中，由Hedgehog和Wnt信号分子控制的两条这样的通路受到化学抑制的后果。这项建议的结果应该为预测和对抗与使用这种治疗试剂相关的有害影响提供一个战略框架。

DESCRIPTION (provided by applicant): An abundance of evidence supports a role for aberrant cellular responses to developmentally important signaling molecules in the biogenesis of cancer. The therapeutic value of agents being developed to target these pathways, such as those controlled by the Hedgehog and Wnt signaling molecules are likely to be diminished in children or child-bearing women due to the dependency of normal developmental processes on these pathways. The long-term goal of our research is to understand the mechanisms that would enable us to target such pathways in disease with minimal consequences to normal developmental processes. In this proposal, we will uncover the interactions of two novel inhibitors of the Hh and Wnt/2-catenin signal transduction pathways with developing tissues in vertebrates using zebrafish as a model organism. In identifying the developmental processes that are influenced by transient exposure to these small molecules, we will establish the necessary knowledgebase to successfully predict and minimize unwanted effects from therapeutic targeting of these developmental and oftentimes cancerous pathways. PUBLIC HEALTH RELEVANCE: In the last decade, significant advances have been made toward achieving chemical control of key developmental signal transduction pathways that are frequently corrupted in cancer. Given the promise of these therapeutic strategies and the perils that they pose for developing individuals, we propose to systematically chronicle the consequences from the chemical inhibition of two such pathways controlled by the Hedgehog and Wnt signaling molecules in vertebrate embryogenesis and adolescent growth. The findings from this proposal should provide a strategic framework for predicting and countering unwanted effects that are associated with the use of such therapeutic reagents.